The goal of this research is to understand the processes that control differentiation of erythroid cells. The method of approach will be to analyze various properties of a permanent Friend leukemia virus-transformed erythroleukemia cell line which can be induced to undergo a characteristic erythroid differentiation in cell culture. By comparing the control of differentiation of these malignant cells with control of normal erythropoiesis, we hope to elucidate how transformation with leukemic viruses alters these processes. We will study what controls are exerted during differentiation on the transcription and utilization of globin mRNA. Studies to date indicate that the initial accumulation of globin mRNA is controlled by increased transcription. Differential accumulation of beta maj and beta min globin mRNAs with different chemical inducers also is controlled at the transcriptional level. In contrast the periodic accumulation and decay of histone mRNA during the cell cycle is controlled primarily by post-transcriptional processes. Cell hybrids expressing human globin genes are being used to study transcription and control of differential gene expression at the human gamma-delta-beta gene locus. Another major area of investigation involves the use of cellular genetics for analyzing control of globin gene expression and the erythroid differentiation pathway. DNA-mediated transformation of cells with cloned globin genes will be used to develop a system for studying potential cisacting regulatory gene sequences. Studies of cell hybrids will lead to a better understanding of an X-linked, transacting locus controlling hemoglobin production. Cell hybrids, mutants and different culture conditions will be used to study the degree of coordinate control of several erythroid traits and to assess the cause-effect relationships in the differentiation pathway. With certain mutants we hope to better understand control of globin gene expression at the molecular level. These studies are relevant to an understanding of altered states of erythropoiesis, including the thalassemias and sideroblastic anemias.